Ann Rheum Dis 2015 Yamamoto e46

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Is rituximab effective for IgG4-related diseasein the long term? Experience of cases treatedwith rituximab for 4 years

A prospective open-label trial of rituximab (RTX) for IgG4-relateddisease (IgG4-RD) was recently described in the Annals of the

Rheumatic Diseasesby Carrutherset al.1According to their results,RTX is effective as induction therapy for IgG4-RD without gluco-

corticoid in the short term. We agree and support their results. Wehave also prescribed RTX for typical cases of IgG4-RD, showingcharacteristics of younger age, experience of several relapses, nohistory of hepatitis B and, since 2011, hesitation to increase thedose of glucocorticoid due to complications. We are currently treat-ing three cases using RTX. Our protocol is as follows. We prescribe500 mg/body of RTX at the onset of relapse. Meanwhile, the doseof glucocorticoid is decreased as much as possible. The patientsvisit our hospital for blood tests once every few months.Whole-body CT is routinely performed once a year. When relapseis suspected, we examine the whole body by CT.

The maximum period of follow-up since initial RTX is cur-rently 4 years. Case 1 involved a 60-year-old Japanese woman.

She presented with IgG4-related dacryoadenitis and sialadenitis,and autoimmune pancreatitis. The initial dose of glucocorticoidwas 40 mg/day, but relapses repeated with the tapering ofsteroid doses. Immunosuppressants were added, but provedineffective and a third relapse was experienced in 2011. RTX

was started because of glucocorticoid-induced avascular necrosisof the femoral heads. The glucocorticoid dose is currently 4 mg/day. Case 2 involved a 42-year-old Japanese woman who ini-tially suffered from IgG4-related dacryoadenitis and sialadenitis.IgG4-related tubulointerstitial nephritis and retroperitonealbrosis occurred during the course. The initial dose of predniso-lone was 30 mg/day, but a third relapse was experienced in2012. In this case, increasing the dose of glucocorticoid wasavoided due to the complication of severe diabetes mellitus.

RTX was started and the dose of prednisolone was decreased to3 mg/day. Case 3 involved a 44-year-old Japanese man. Thepatient showed lesions of the lacrimal and salivary glands, pan-creas and lungs. The initial dose of steroid was 30 mg/day. Thepatient experienced two relapses despite a combination ofimmunosuppressants, such as methotrexate and cyclophospha-mide. We administered RTX in 2013 due to impaired glucosetolerance. The dose of prednisolone is currently 4 mg/day(table 1). Adverse events were only seen in case 1, as herpeszoster, and the other patients showed no problems.2

Figure 1shows serial changes in serum levels of IgG4 and thepercentage of CD19+ lymphocytes among all lymphocytes afterinitial RTX prescription in these three cases. After the initial

administration of RTX,

ve relapses were seen in case 1, two incase 2 and one in case 3. Levels of serum IgG4 after RTXtherapy were elevated at relapse in case 1. The percentage ofCD19+ lymphocytes was also elevated at relapse. In case 2,serum IgG4 levels were not elevated at rst relapse after RTX

Table 1 Profiles of patients with IgG4-related disease treated with RTX

C ase Age, sex OOI Compl ications

Initialdose ofPSL Immunosuppressants

Times ofrelapse

Pre-treatmentof RTX

Timesof RTX

Period offollow-up(months)

Treatmentat this point

1 60F AIP G-AVN 40 CsA, MZR 3 PSL 16+MZR 6 48 PSL 4

2 42F TIN, RF DM 30 AZA 3 PSL 15+AZA 3 35 PSL 3

3 44M AIP, PI 30 MTX, MZR, CY 2 PSL 14 1 24 PSL 4

AIP, autoimmune pancreatitis; AZA, azathioprine; CsA, cyclosporine A; CY, cyclophosphamide; DM, diabetes mellitus; G-AVN, glucocorticoid-induced avascular necrosis of femoral head;MTX, methotrexate; MZR, mizoribin; OOI, other organ involvements; PI, pulmonary involvement; PSL, prednisolone; RF, retroperitoneal fibrosis; RTX, rituximab; TIN, tubulointerstitialnephritis.

Figure 1 Serial changes in levels ofserum IgG4 and percentage ofCD19-positive lymphocytes at eachvisit after rituximab treatment.

Ann Rheum DisAugust 2015 Vol 74 No 8 e46

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administration. On the other hand, CD19+ lymphocytes wereincreased, with a large uctuation in range at both relapses.Case 3 did not present with elevated serum IgG4 concentrationat relapse, but B cells were increased. With regard to case 1,which was treated multiple times with RTX, this treatment hasrecently tended to be less effective against IgG4-RD. The periodof efcacy has become extremely short, instead of transitional.In this case, re-biopsy of lacrimal gland was performed, anddevelopment towards malignant lymphoma was ruled out. We

performed further examination for anti-RTX antibody, butresults were negative. The pathogenesis of case 1 has beenshown to shifted towards RTX resistance.

The outcomes of our cases treated with RTX over the longterm suggest two points. First, the indication for RTX to treatIgG4-RD is a denitive case3 diagnosed by histological examin-ation, younger age, no history of hepatitis B and cases in whichincreasing the glucocorticoid dose is difcult due to complica-tions. Second, one or two administrations of RTX cannotinduce or maintain complete remission of IgG4-RD for long,and some cases present with attenuation of the RTX effect. Thepathogenesis of IgG4-RD needs to be analysed and elucidated,4

and new treatment strategies need to be developed for

RTX-resistant cases.Motohisa Yamamoto,1 Teruhito Awakawa,2 Hiroki Takahashi1

1Division of Rheumatology and Clinical Immunology, Sapporo Medical UniversitySchool of Medicine, Sapporo, Japan2Department of Internal Medicine and Gastroenterology, Sapporo DohkohkaiHospital, Sapporo, Japan

Correspondence toDr Motohisa Yamamoto, Division of Rheumatology andClinical Immunology, Sapporo Medical University School of Medicine, South1-West 16, Chuo-ku, Sapporo, Hokkaido 0608543, Japan; [email protected]

Acknowledgements We wish to thank Yui Shimizu, Hidetaka Yajima and ChisakoSuzuki at Sapporo Medical University for the medical care of these cases.

Contributors MY, TA and HT contributed equally to the conception and drafting ofthe manuscript.

Competing interests None.

Ethics approval The Sapporo Medical University Hospital Institutional ReviewBoard approved this study.

Patient consent Obtained.

Provenance and peer review Commissioned; internally peer reviewed.

To cite Yamamoto M, Awakawa T, Takahashi H. Ann Rheum Dis 2015;74:e46.

Received 20 March 2015Accepted 23 March 2015Published Online First 10 April 2015

http://dx.doi.org/10.1136/annrheumdis-2015-207640

Ann Rheum Dis2015;74:e46. doi:10.1136/annrheumdis-2015-207625

REFERENCES1 Carruthers MN, Topazian MD, Khosroshahi A, et al. Rituximab for IgG4-related

disease: a prospective, open-label trial. Ann Rheum Dis 2015. Published Online First:9 February 2015. doi:10.1136/annrheumdis-2014-206605

2 Yamamoto M, Yajima H, Takahashi H, et al. Everyday clinical practice in IgG4-relateddacryoadenitis and/or sialadenitis: results from the SMART database. Mod Rheumatol2015;25:199204.

3 Umehara H, Okazaki K, Masaki Y,et al. Comprehensive diagnostic criteria forIgG4-related disease (IgG4-RD), 2011. Mod Rheumatol2012;22:2130.

4 Yamamoto M, Takahashi H, Shinomura Y. Mechanisms and assessment ofIgG4-related disease: lessons for the rheumatologist. Nat Rev Rheumatol2014;10:14859.

e46 Ann Rheum DisAugust 2015 Vol 74 No 8

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http://dx.doi.org/10.1136/annrheumdis-2015-207640http://dx.doi.org/10.3109/14397595.2014.950036http://dx.doi.org/10.3109/s10165-011-0571-zhttp://dx.doi.org/10.1038/nrrheum.2013.183http://group.bmj.com/http://group.bmj.com/http://ard.bmj.com/http://group.bmj.com/http://ard.bmj.com/http://dx.doi.org/10.1038/nrrheum.2013.183http://dx.doi.org/10.3109/s10165-011-0571-zhttp://dx.doi.org/10.3109/14397595.2014.950036http://dx.doi.org/10.1136/annrheumdis-2015-207640http://crossmark.crossref.org/dialog/?doi=10.1136/annrheumdis-2015-207625&domain=pdf&date_stamp=2015-04-10


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yearswith rituximab for 4treatedin the long term? Experience of cases

Is rituximab effective for IgG4-related disease

Motohisa Yamamoto, Teruhito Awakawa and Hiroki Takahashi

doi: 10.1136/annrheumdis-2015-2076252015 74: e46 originally published online April 10, 2015Ann Rheum Dis

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